Caridac arrhythmias and their treatment remain major public health problems in the United States. We intend to investigate systematically the changes in passive and active membrane properties that underly arrhythmogenesis and the electropharmacologic actions of antiarrhythmic drugs. We will employ the multiple microelectrode techniques of intracellular current application and voltage clamping in the cardiac Purkinje fiber. These techniques permit selective control of numerous electrophysiologic variables and allow direct assessment of the determinants of cardiac excitability such as membrane ionic conductances, active membrane generator properties, cable properties and other passive membrane characterisitics. Although these techniques have been available for some time and have been instrumental in advancing our knowledge of basic cardiac electrophysiology, they have been little used in the study of either arrhythmogenesis or the action of antiarrhythmic drugs except by the applicant and a few others. This investigation will be of both basic scientific and clinical significance. Our earlier work demonstrated that these methods elucidate fundamental mechanisms by which antiarrhythmic drugs work, which, in the final analysis result from alterations in ionic currents as mediated by ionic conductances and driving forces. This proposal will extend our understanding of the actions of antiarrhythmic drugs both in normal tissues and in tissues exposed to arrhymogenesis and antiarrhythmic drugs that are both electrophysiologically sound and clinically useful can be developed. Computer modeling of membrane events will be used to assess the magnitude of error in the measurements and otherwise assist in data interpretation. Comparison of the model with experimental data and vice versa may, in the long run, facilitate the characterization of drugs that may have good antiarrhythmic potential.